Periodically we do updates on the iPS cell field and now seems like a good time. Where do things stand?

Here’s my top 5 list of action items for the iPS cell field in the coming year.

5.) Methods on the brain. A significant fraction, some would argue too high a fraction, of iPS cell papers will be methodological in the coming year. Depending on the author, some of these are likely to be published in very high profile journals. Will any be truly transformative in the coming year? I’m a bit skeptical overall that we will get to an all-chemical method in the coming year. I am hopeful that the miRNA-based approach might take off. Either way, despite some folks’ frustration with the incremental nature of the science involved in the evolving iPS cell methodology, it is still an essential area for improvement.

4.) Transdifferentiation take over? Many in the stem cell community are just as excited about transdifferentiation as they are about iPS cells. Some are in fact more excited about transdifferentiation. Why not avoid the “middle man” of iPS cells, they ask. I personally think transdifferentiation has enormous potential, but I’m betting that for some areas, for generating some types of differentiated cells, iPS cells are going to be needed. Even so, transdifferentiation is likely to continue to excite in the coming year and you can expect more action in this area. Like so many things, when it comes to iPS cells versus transdifferentiation, it is not an “either or” proposition. We want and need both!

3.) iPS cells: we’ll take them, warts and all. In the past year, it has become clear that iPS cells are not perfect as they contain genomic and epigenomic differences compared to ES cells as well as to the “parental” cells from which the iPS cells were made. Some of these differences are even associated with cancer-related genes. However, we still do not know the meaning of these differences and of the mutations in iPS cells. It seems likely that at least some of the mutations and differences will have functional meaning, but a key area in the coming year will be mapping out the meaning of these differences. All along most stem cell researchers were not under any illusions that iPS cells were perfect, but certainly there was some over-exuberance about them. From my perspective, despite the molecular “warts” in iPS cells, they are still extraordinarily exciting and their potential remains great.

2.) Efficiency becomes a lower priority and clinical usefulness takes over. As discussed above, a lot of folks are hammering away at trying to make better methods for producing iPS cells with “better” meaning in most cases, higher efficiency, non-genetic methods. However, as we discussed in our perspectives piece in Cell Stem Cell last week, we argue for a shift in priorities. What is most important now is making iPS cells with higher clinical potential even at the potential cost of lower efficiency. So we need to end our pre-occupation with boosting efficiency and refocus on how we might make iPS cells with the best clinical potential. A key part of this will be finding new ways to preserve the genome and epigenome of cells during the reprogramming process.

And what’s the #1 action item for the iPS cell field in the coming year?

1.) How tumorigenic are iPS cells? I would argue, perhaps not surprisingly given my background in tumor biology, that the top priority at this point is to figure out just how tumorigenic iPS cells and their derivatives are in clinical relevant transplantation-like models. There remain, 5 years into the history of iPS cells, few studies that have any transplantation/clinical significance on the tumorigenicity of iPS cells.

It is time to stop asking questions such as how well mice survive that were derived from iPS cells using genetics. That has little if any clinical significance unless anyone is planning to clone humans from iPS cells, which I do not think is on the agenda. In addition, the traditional teratoma assay, while wonderfully useful and indeed a tumor assay more than a pluripotency assay, is not a substitute for clinically relevant studies. How often are humans going to be treated subcutaneously with iPS cells? Never.

What do I mean by “clinically relevant”? For example, if you are going to treat a neurological disorder, you do not study the tumorigenicity of your iPS cells or their derivatives by teratoma assays or by deriving mice from the iPS cells. Instead you inject the cells into the mouse brain or spinal cord in a manner as closely mimicking how the cells would be transplanted into a human. Then you study them. If you are studying the heart, you inject cells into the heart. And so on.

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Good list. The only thing I would have added, possibly prematurely, would be the potential for more high profile papers upcoming about in vitro drug discovery. The Nature paper last year on modelling schizophrenia in a dish using IPS cells is right on this topic, as this kind of study would be the logical next step. It seems to me that this is the direction a lot of the pharma companies are trying to go in paying academics to do research for them. I just left a high profile lab at Sloan Kettering, and my former PI mentioned to me that, as opposed to his earlier research on cell based therapies for parkinsons, all the big companies want to see him using IPScells as a tool for drug discovery. And when the money is coming in… well, you can’t really say no.

On transdifferenciation: while it might be interesting for some approaches, wouldn’t the relatively limited ammount of cells gotten this way limit its usefulness? I would think that the capability of pluripotent stem cells (of whatever source and method) to proliferate without limits would give them an edge.

Hi John,
Your question is a good one. I think the answer is that it is not clear that when you do transdifferentiation that you can get cells that can proliferate that well, whereas iPSC are immortal. For cell therapy you need a lot of cells and along the way you are likely to lose some by sorting, etc.
Paul